We have demonstrated that highly active antiretroviral therapy based structured treatment interruptions (STI-HAART)can boost SIV-specific immune responses, thereby reducing the viral rebound rate and inducing immune control of SIV in acutely SIV251-infected macaques. However, during chronic infection, characterized by impaired immune functions, STI-HAART does not induce immune control. To reconstitute virus-specific immunity we have developed a novel topical therapeutic DNA vaccine, called DermaVir. Application of DermaVir to the surface of the skin of mice and macaques resulted in transduction of Langerhans cells, migration of these cells into lymph nodes, gene expression by genetically modified dendritic cells, and induction of vigorous, virus-specific T cell-mediated immune responses. In chronically SIVmac2sl-infectedmacaques and in macaques with late-stage disease, i.e. AIDS, DermaVir, in combination with STI-HAART, reduced viral rebound to a rate comparable to that observed during STI-HAART alone during primary infection. These unexpected and exciting initial results warrant further investigation of the effects of DermaVir on immune control of HIV. We propose to evaluate various aspects of this novel therapeutic modality in the same SIV251-infected macaque model to create the basis for moving to the clinical stage of development. In this project we intend to explore whether vaccine potency can be enhanced by the use of molecular adjuvants. Initial studies in mice will serve to determine the optimal dose and combination of IL-1 5and CD40L with DermaVir immunization. A comparative study will follow to evaluate the effects of these adjuvants to therapeutic immunization on control of viremia in rhesus macaques with chronic SIV infection on STI-HAART. Additionally, we propose to study the virus-specific humoral and cellular immune responses to DermaVir during the proposed primate trial in order to establish immune correlates of virus control. Specific Aim 1: Preliminary testing of molecular adjuvants to enhance the potency of DermaVir in the murine model. Specific Aim 2: Comparative analysis of molecular adjuvants in combination with DermaVir therapeutic vaccination in non-human primates. Specific Aim 3: Study of immune correlates of viral control during therapeutic immunization in non-human primates.